Cancer is one of the leading causes of death known today, and effective treatment of many solid tumors still remains elusive. It is believed that novel antitumor drugs possessing a strong inhibitory effect on ribonucleotide reductase, an essential enzyme for cellular replication would be a useful addition to present drug regimens for treating cancer.
It is well-known that the reductive conversion of ribonucleotides to the corresponding deoxyribonucleotides is a key step in the biosynthesis of DNA. Since deoxyribonucleotides are present in extremely low levels in mammalian cells, investigators have assumed that an inhibitor of ribonucleotide reductase could be more effective than an inhibitor of DNA polymerase in blocking DNA synthesis. See, Cory and Chiba, "Combination Chemotherapy Directed at the Components of Nucleoside Diphosphate Reductase", Inhibitors of Ribonucleoside diphosphate reductase Activity, Cory, J. G. and Cory, A. M. Eds.; Pergamon Press: Oxford, 1989; pp 245-264. Consequently, through this work it was believed that the development of strong inhibitors of ribonucleotide reductase would create potential powerful weapons against cancer.
For many years, studies of novel .alpha.-(N)-heterocyclic carboxaldehyde thiosemicarbazones (HCTs), a class of the most potent inhibitors of ribonucleoside diphosphate reductase, has attracted considerable interest. A variety of HCTs such as 5-hydroxypyridine-2-carboxaldehyde thiosemicarbazone (5 HP), 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ-1), 5-(acetylamino)pyridine-2-carboxaldehyde thiosemicarbazone (5-AAP), 3- and 5-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP and 5-AP) and their 4-methyl derivatives (3-AMP and 5-AMP), 3- and 5-hydroxy-4-methylpyridine-2-carboxaldehyde thiosemicarbazone (3-HMP and 5-HMP) have been reported. See, DeConti, et al., Cancer Res., 1972, 32, 1455-1462; Agrawal, et al., J. Med. Chem. 1976, 19, 970-972; French, et al., J. Med. Chem., 1974, 17, 172-181; Liu, et al., J. Med. Chem. 1992, 35, 3672-3677; Wang, et al., J. Med. Chem. 1992, 35, 3667-3671.
Structure-activity relationship studies of a series of HCTs revealed that both 3-AP and 3-AMP showed much better therapeutic effects against L1210 leukemia, M-109 lung carcinoma and A2780 human ovarian carcinoma than other HCTs reported to date. Liu, et al., J. Med. Chem. 1992, 35, 3672-3677; Agrawal, et al., "The Chemistry and Biological Activity of the .alpha.-(N)-Heterocyclic Carboxaldehyde Thiosemicarbazones." Progress in Medicinal Chemistry; Ellis, G. P.; West, G. B., Eds.; Elsevier/North-Holland Biomedical Press: New York, 1978; Vol. 15, pp 321-356. In addition, 3-AP and 3-AMP are potent agents with significant antineoplastic activity in comparison with hydroxyurea (HU), an approved ribonucleotide reductase inhibitor used in clinics. The study of these compounds on a much larger scale has necessitated scale-up production of these agents.
As outlined in FIG. 1, the first syntheses of 3-AP and 3-AMP were accomplished in Dr. Alan Sartorelli's laboratories at Yale University. Although the previous synthesis has the advantage of low cost of the materials used in the synthetic procedure, the scheme has proved to be troublesome due to long reaction sequences, low yields and difficult handling. For this reason, the present inventors investigated the synthesis and have developed new methods to prepare 3-AP and 3-AMP.